Celiac disease (according to ICD-10, WHO 2006 version: K90.0), also referred to as gluten-sensitive or gluten-induced enteropathy, intestinal infantilism; or non-tropical or endemic sprue, gluten intolerance or Heubner-Herter disease in adults, is a chronic disease of the small intestinal mucosa resulting from a hypersensitivity to gluten, a protein which is found in many types of grains. The intolerance remains throughout life and is in part genetically determined and cannot at present be treated causally.
Foods containing gluten give rise to inflammation of the small intestinal mucosa with frequently extensive destruction of the intestinal epithelial cells, so that nutrients are poorly absorbed and remain undigested in the bowels. Accordingly, the symptoms are weight loss, diarrhea, vomiting, anorexia, fatigue, ill-humor and, not least, failure to thrive during infancy. The severity of the condition can vary widely, making early diagnosis more difficult. Untreated celiac disease increases the risk of occurrence of non-Hodgkin lymphoma as well as carcinomas of the digestive tract, such as intestinal cancer. At present, the only treatment of celiac disease consists in gluten-free diet.
Meanwhile, a number of harmful peptide fragments of gluten have been identified. They all belong to the alcohol-soluble fraction (so-called prolamins) and are referred to as gliadin. In susceptible individuals, these peptide fragments give rise to a complex reaction of the intestinal mucosa and immune system. Mucosal cells of the small intestine produce increasing amounts of various classes of HLA (HLA-I, -DR and -DQ). Certain gliadin peptides bind to the HLA-DQ2 produced in increasing amounts. Said binding is increased as a result of glutamic acid formation from the amino acid glutamine which is present in the peptide in large numbers.
Formation of glutamic acid is mediated by the tissue transglutaminase enzyme, in particular tissue transglutaminase 2 (tTG2). As a result of this change, the corresponding section of gliadin has a better fit in the “pockets” of HLA proteins. The complex of gliadin peptide and HLA-DQ2 in turn binds to CD4+ T helper cells, causing increased production of various inflammatory mediators therein, for instance interferon-γ, TNFα, interleukin-6 and interleukin-2. Various antibodies are formed during the further process of inflammation. In addition to antibodies against gliadin peptides themselves (gliadin antibodies, AGA), there are so-called autoantibodies against endogenous antigens. Tissue transglutaminase, particularly tTG2, has been identified as primarily responsible autoantigen. In view of these findings, celiac disease in pathophysiological terms is understood to be a mixed form of allergy and autoimmune disease, wherein the allergic component in the form of hypersensitivity to the exogenous gliadin protein represents the precipitating factor, while the autoimmune response to endogenous structures is responsible for the severity of symptoms. Ultimately, the inflammatory process results in apoptosis of enterocytes, eventually leading to a more or less pronounced loss of small intestinal villi. As a result of the reduced absorption surface, the small intestinal mucosa damaged in this way is no longer capable of sufficiently transferring the supplied foods into the bloodstream.
In general, serological diagnostics of celiac disease involves testing for the presence of IgA and/or IgG type antibodies to gliadin or tTG2. One problem of well-known diagnostic markers is that the sensitivity of the tests is not yet optimal. Particularly the tests for the presence of gliadin antibodies exhibit low sensitivities of less than 80%. While well-known tests for tTG2 antibodies are more sensitive on the whole, the informative epitopes of tTG2 are so-called conformational epitopes, i.e. epitopes that can be recognized by antibodies only if tTG2 is presented in a non-denatured state. Consequently, tests for tTG2 antibodies are limited to those test methods wherein the tTG2 antigen is presented in a non-denatured state.